TY - JOUR
T1 - Does methylmercury-induced hypercholesterolemia play a causal role in its neurotoxicity and cardiovascular disease?
AU - Moreira, Eduardo Luiz
AU - De oliveira, Jade
AU - Dutra, Márcio Ferreira
AU - Santos, Danúbia Bonfanti
AU - Gonçalves, Carlos Alberto
AU - Goldfeder, Eliane Maria
AU - De bem, Andreza Fabro
AU - Prediger, Rui Daniel
AU - Aschner, Michael
AU - Farina, Marcelo
N1 - Funding Information:
Brazilian institutions Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); the Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC); Programa de Apoio aos Núcleos de Excelência (PRONEX—Project NENASC); IBN-Net/CNPq, INCT (Instituto Nacional de Ciência e Tecnologia) for Excitotoxicity and Neuroprotection; CNPq-Brazil to C.A.G., A.F.B., R.D.S.P., and M.F.; National Institute of Environmental Health Science (ES R01 07331; ES P30 000267 to M.A.).
PY - 2012/12
Y1 - 2012/12
N2 - Methylmercury (MeHg) is an environmental pollutant that biomagnifies throughout the aquatic food chain, thus representing a toxicological concern for humans subsiding on fish for their dietary intake. Although the developing brain is considered the critical target organ of MeHg toxicity, recent evidence indicates that the cardiovascular system may be the most sensitive in adults. However, data on the mechanisms mediating MeHg-induced cardiovascular toxicity are scarce. Based on the close relationship between cardiovascular disease and dyslipidemia, this study was designed to investigate the effects of long-term MeHg exposure on plasma lipid levels in mice, as well as their underlying mechanisms and potential relationships to MeHg-induced neurotoxicity. Our major finding was that long-term MeHg exposure induced dyslipidemia in rodents. Specifically, Swiss and C57BL/6 mice treated for 21 days with a drinking solution of MeHg (40mg/l, ad libitum) diluted in tap water showed increased total and non-HDL plasma cholesterol levels. MeHg-induced hypercholesterolemia was also observed in low-density lipoprotein receptor knockout (LDLr-/-) mice, indicating that this effect was not related to decreased LDLr-mediated cholesterol transport from blood to other tissues. Although the hepatic synthesis of cholesterol was unchanged, significant signs of nephrotoxicity (glomerular shrinkage, tubular vacuolization, and changed urea levels) were observed in MeHg-exposed mice, indicating that the involvement of nephropathy in MeHg-induced lipid dyshomeostasis may not be ruled out. Notably, Probucol (a lipid-lowering drug) prevented the development of hypercholesterolemia when coadministered with MeHg. Finally, hypercholesterolemic LDLr-/- mice were more susceptible to MeHg-induced cerebellar glial activation, suggesting that hypercholesterolemia in itself may pose a risk factor in MeHg-induced neurotoxicity. Overall, based on the strong and graded positive association between total as well as LDL cholesterol and risk of cardiovascular diseases, our data support the concept of MeHg-induced cardiovascular toxicity.
AB - Methylmercury (MeHg) is an environmental pollutant that biomagnifies throughout the aquatic food chain, thus representing a toxicological concern for humans subsiding on fish for their dietary intake. Although the developing brain is considered the critical target organ of MeHg toxicity, recent evidence indicates that the cardiovascular system may be the most sensitive in adults. However, data on the mechanisms mediating MeHg-induced cardiovascular toxicity are scarce. Based on the close relationship between cardiovascular disease and dyslipidemia, this study was designed to investigate the effects of long-term MeHg exposure on plasma lipid levels in mice, as well as their underlying mechanisms and potential relationships to MeHg-induced neurotoxicity. Our major finding was that long-term MeHg exposure induced dyslipidemia in rodents. Specifically, Swiss and C57BL/6 mice treated for 21 days with a drinking solution of MeHg (40mg/l, ad libitum) diluted in tap water showed increased total and non-HDL plasma cholesterol levels. MeHg-induced hypercholesterolemia was also observed in low-density lipoprotein receptor knockout (LDLr-/-) mice, indicating that this effect was not related to decreased LDLr-mediated cholesterol transport from blood to other tissues. Although the hepatic synthesis of cholesterol was unchanged, significant signs of nephrotoxicity (glomerular shrinkage, tubular vacuolization, and changed urea levels) were observed in MeHg-exposed mice, indicating that the involvement of nephropathy in MeHg-induced lipid dyshomeostasis may not be ruled out. Notably, Probucol (a lipid-lowering drug) prevented the development of hypercholesterolemia when coadministered with MeHg. Finally, hypercholesterolemic LDLr-/- mice were more susceptible to MeHg-induced cerebellar glial activation, suggesting that hypercholesterolemia in itself may pose a risk factor in MeHg-induced neurotoxicity. Overall, based on the strong and graded positive association between total as well as LDL cholesterol and risk of cardiovascular diseases, our data support the concept of MeHg-induced cardiovascular toxicity.
KW - Cardiovascular disease
KW - Cholesterol
KW - Dyslipidemia
KW - Low-density lipoprotein receptor
KW - Methylmercury
KW - Neurotoxicity
UR - http://www.scopus.com/inward/record.url?scp=84869417613&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84869417613&partnerID=8YFLogxK
U2 - 10.1093/toxsci/kfs252
DO - 10.1093/toxsci/kfs252
M3 - Article
C2 - 22903822
AN - SCOPUS:84869417613
SN - 1096-6080
VL - 130
SP - 373
EP - 382
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 2
ER -